PROJECT SUMMARY Alzheimer disease (AD) is the leading cause of dementia in the elderly and occurs in all ethnic and racial groups. A multitude of genetic studies in AD have identified multiple AD associated genes and loci, but a large portion of the genetic contribution to AD remains unknown. The Alzheimer Disease Sequencing Project (ADSP) is using large-scale sequencing efforts to increase our knowledge about the genetic variation that influences AD, particularly rare genetic variants that enhance AD risk or protect against AD. In the most recent wave of funding, ADSP is sequencing individuals from the ADSP Follow-up Study (FUS) through AG057659 and through the pending application, AG062943. The Genomic Centers for Alzheimer's Disease (GCAD) is joint-calling these data along with the original ADSP Discovery and Extension data and additional datasets. These efforts are important to providing harmonized data for the discovery of AD genes. This competitive revision application (responding to PAR-18-890) of our funded cooperative agreement the AG057659 (funded under PAR-16-406) is designed to generate high-quality sequence data in this follow-up sample. The goals of this application are to perform additional sequencing of 3400 new individuals from key cohorts, to accelerate ongoing quality control (QC) activities and to support QC activities for additional datasets not originally included in the peer-reviewed FUS application. Key to the success of the ADSP analyses is careful and comprehensive QC of the sequence data. The specific aims of this competitive revision application (PAR-18-890) address the need for QC and quality assurance (QA) of ~18,000 samples from the FUS that is not currently funded through other sources. Drs. Martin and Naj have led the development of the QC protocols and the implementation of the current QC protocols for the ADSP, conducted by the HIHG Center for Genetic Epidemiology and Statistical Genetics (CGESG) and University of Pennsylvania Neurodegeneration Genomics Center (PNGC) QC teams. In this proposal, we request supplemental funding to accelerate ongoing QC activities and to support QC activities that are beyond the scope of current funding. These funds will support the processing of samples through the QC pipeline, and the necessary QA steps as the ADSP integrates protocols with Uniformed Services University of the Health Sciences (USUHS) as a sequencing center. In addition, the multi-ethnic nature of the FUS dataset requires us to adapt the QC protocol, developed for primarily non-Hispanic white datasets. To meet these immediate needs, we propose to 1) Conduct additional whole genome sequencing of 3400 new individuals from key cohorts, 2) Adapt the ADSP QC pipeline to process whole genome data from USUHS and harmonize these with previous ADSP data, 3) Explore impacts of changing sequence technologies, bioinformatics pipelines and sequence builds on pre- and post-QC datasets through analysis of replicate samples, 4) Develop appropriate protocols for reporting metrics and error detection in the multiple multiethnic datasets in the FUS, 5) Conduct QC of all FUS and new samples handled by GCAD.